Mitochondria are crucial for cellular metabolism and signalling. Mitochondrial activity is modulated by mitochondrial fission and fusion, which are required to properly balance metabolic functions, transfer material between mitochondria, and remove defective mitochondria. Mitochondrial fission occurs at mitochondria-endoplasmic reticulum (ER) contact sites, and requires the formation of actin filaments that drive mitochondrial constriction and the recruitment of the fission protein DRP1. The role of actin in mitochondrial fusion remains entirely unexplored. Here we show that preventing actin polymerisation on either mitochondria or the ER disrupts both fission and fusion. We show that fusion but not fission is dependent on Arp2/3, whereas both fission and fusion require INF2 formin-dependent actin polymerization. We also show that mitochondria-associated actin marks fusion sites prior to the fusion protein MFN2. Together, our work introduces a method for perturbing organelle-associated actin and demonstrates a previously unknown role for actin in mitochondrial fusion.

Emerging evidence indicates that the TRPM8 channel plays an important role in prostate cancer (PCa) progression, by impairing the motility of these cancer cells. Here, we reveal a novel facet of PCa motility control via direct protein-protein interaction (PPI) of the channel with the small GTPase Rap1A. The functional interaction of the two proteins was assessed by active Rap1 pull-down assays and live-cell imaging experiments. Molecular modeling analysis allowed the identification of four putative residues involved in TRPM8-Rap1A interaction. Point mutations of these sites impaired PPI as shown by GST-pull-down, co-immunoprecipitation, and PLA experiments and revealed their key functional role in the adhesion and migration of PC3 prostate cancer cells. More precisely, TRPM8 inhibits cell migration and adhesion by trapping Rap1A in its GDP-bound inactive form, thus preventing its activation at the plasma membrane. In particular, residues E207 and Y240 in the sequence of TRPM8 and Y32 in that of Rap1A are critical for the interaction between the two proteins not only in PC3 cells but also in cervical (HeLa) and breast (MCF-7) cancer cells. This study deepens our knowledge of the mechanism through which TRPM8 would exert a protective role in cancer progression and provides new insights into the possible use of TRPM8 as a new therapeutic target in cancer treatment.

Polycomb repressive complex 2 (PRC2) mediates histone H3K27me3 methylation and the stable transcriptional repression of a number of gene expression programs involved in the control of cellular identity during development and differentiation. Here, we report on the generation and on the characterization of a zebrafish line harboring a null allele of eed, a gene coding for an essential component of the PRC2. Homozygous eed-deficient mutants present a normal body plan development but display strong defects at the level of the digestive organs, such as reduced size of the pancreas, hepatic steatosis, and a loss of the intestinal structures, to die finally at around 10–12 days post fertilization. In addition, we found that PRC2 loss of function impairs neuronal differentiation in very specific and discrete areas of the brain and increases larval activity in locomotor assays. Our work highlights that zebrafish is a suited model to study human pathologies associated with PRC2 loss of function and H3K27me3 decrease.

Près de 90 % des décès chez les patients atteints d'un cancer du sein sont imputables à la formation de métastases. Le cancer du sein triple négatif (TN) se distingue par sa nature agressive et sa forte propension à métastaser. Parmi les différents sites touchés, le développement de métastases cérébrales présente le pronostic le plus sombre et altère considérablement la qualité de vie des patients. Les mécanismes qui sous-tendent la progression des métastases cérébrales dans le cancer du sein triple négatifne sont à ce jour décrits que de façon parcellaire. Pour tenter de mieux les comprendre, ce travail vise à étudier le comportement des cellules du cancer du sein au cours du processus de dissémination vers le cerveau. Pour cela il s’est agit de développer différents modèles expérimentaux complémentaires : Un modèle in vitro de barrière hémato-encéphalique humaine (BHE), de matrice extracellulaire organotypique3D in vitro, des co-cultures ex vivo de tranches de cerveau de souris et des expériences de xénogreffes in vivo. Dans ces travaux, nous démontrons l'implication de TrkA et de ses co-récepteurs (e.g. EphA2) dans le développement des métastases cérébrales.Nous avons tout d’abord identifié le complexe de récepteur TrkA/EphA2 comme médiateur de la transmigration de la BHE induite par le proNGF. Par ailleurs, nos résultats ont également démontré que l'inhibition combinée de TrkA et d'EphA2 réduirait de manière significative les métastases cérébrales dans un modèle pré-clinique de cancer du sein.Ces résultats remettent en question la compréhension actuelle des mécanismes de métastases cérébrales et mettent en lumière le rôle du proNGF en tant que facteur clé du tropisme cérébrale du cancer du sein TN.